■额颞叶痴呆(FTD)是早发性痴呆的最常见原因,其中10-20%的病例是由以下三个基因之一的突变引起的:GRN,C9orf72或MAPT。为了有效开发FTD的治疗方法,识别和表征生物标志物以了解疾病的发病机制和评估特定治疗策略对靶生物学和潜在疾病病理的影响是至关重要的。此外,跟踪这些生物标志物在整个疾病进展过程中的纵向变化对于辨别它们与临床表现的相关性以及潜在的预后用途至关重要.
■我们对指示溶酶体生物学的生物标志物进行了全面研究,胶质细胞活化,来自非携带者对照的脑脊液(CSF)和血浆中的突触和神经元健康,零星的FTD(症状性非携带者)和GRN突变的症状携带者,C9orf72或MAPT,以及无症状GRN突变携带者。我们还评估了GRN突变携带者中生物标志物的纵向变化。此外,我们检测了来自散发性FTD和有症状GRN携带者的疾病影响脑区的生物标志物水平,包括颞中回(MTG)和额上回(SFG)以及未受疾病影响的枕下回(IOG).
■我们证实了葡萄糖鞘氨醇(GlcSph),由颗粒蛋白前体调节的溶酶体生物标志物,在来自GRN突变携带者的血浆中升高,有症状和无症状。GlcSph和其他溶酶体生物标志物如神经节苷脂GM2和球苷GB3在散发性FTD和症状性GRN突变携带者受疾病影响的SFG和MTG区域中增加,但不是在IOG中,与对照组的相同大脑区域相比。无症状GRN携带者血浆中的胶质生物标志物GFAP和CSF中的YKL40升高,和所有有症状的群体,除了有症状的C9orf72突变组。来自散发性FTD和症状性GRN突变携带者的SFG和MTG区域的YKL40也增加。CSF和血浆中神经元损伤和变性生物标志物NfL,在所有形式的FTD患者中,CSF中的UCHL1升高。突触生物标志物NPTXR,所有形式的FTD患者的CSF中NPTX1/2和VGF均减少,在有症状的MAPT突变携带者中观察到最明显的减少。此外,我们证明,在FTD的遗传形式中,通过CDR+NACCFTLDSB测量,血浆NfL与疾病严重程度呈显著正相关,在有症状的GRN和MAPT突变携带者中,CSFNPTXR与CDR+NACCFTLDSB呈显著负相关.
■总而言之,我们的全面调查复制了指示溶酶体功能的生物流体生物标志物的改变,胶质激活,FTD的零星和遗传形式的突触和神经元健康,并揭示了GRN突变患者脑组织内这些生物标志物失调的新见解。观察到的生物标志物与疾病严重程度之间的相关性为临床试验中的预后应用和药物功效指标开辟了有希望的途径。我们的数据还暗示了生物流体和组织生物标志物变化之间的复杂关系,未来的研究应该深入研究这些生物标志物的机理基础。这将为FTD靶向治疗的发展奠定基础。
UNASSIGNED: Frontotemporal dementia (FTD) is the most common cause of early-onset dementia with 10-20% of cases caused by mutations in one of three genes: GRN, C9orf72, or MAPT. To effectively develop therapeutics for FTD, the identification and characterization of biomarkers to understand disease pathogenesis and evaluate the impact of specific therapeutic strategies on the target biology as well as the underlying disease pathology are essential. Moreover, tracking the longitudinal changes of these biomarkers throughout disease progression is crucial to discern their correlation with clinical manifestations for potential prognostic usage.
UNASSIGNED: We conducted a comprehensive investigation of biomarkers indicative of
lysosomal biology, glial cell activation, synaptic and neuronal health in cerebrospinal fluid (CSF) and plasma from non-carrier controls, sporadic FTD (symptomatic non-carriers) and symptomatic carriers of mutations in GRN, C9orf72, or MAPT, as well as asymptomatic GRN mutation carriers. We also assessed the longitudinal changes of biomarkers in GRN mutation carriers. Furthermore, we examined biomarker levels in disease impacted brain regions including middle temporal gyrus (MTG) and superior frontal gyrus (SFG) and disease-unaffected inferior occipital gyrus (IOG) from sporadic FTD and symptomatic GRN carriers.
UNASSIGNED: We confirmed glucosylsphingosine (GlcSph), a
lysosomal biomarker regulated by progranulin, was elevated in the plasma from GRN mutation carriers, both symptomatic and asymptomatic. GlcSph and other
lysosomal biomarkers such as ganglioside GM2 and globoside GB3 were increased in the disease affected SFG and MTG regions from sporadic FTD and symptomatic GRN mutation carriers, but not in the IOG, compared to the same brain regions from controls. The glial biomarkers GFAP in plasma and YKL40 in CSF were elevated in asymptomatic GRN carriers, and all symptomatic groups, except the symptomatic C9orf72 mutation group. YKL40 was also increased in SFG and MTG regions from sporadic FTD and symptomatic GRN mutation carriers. Neuronal injury and degeneration biomarkers NfL in CSF and plasma, and UCHL1 in CSF were elevated in patients with all forms of FTD. Synaptic biomarkers NPTXR, NPTX1/2, and VGF were reduced in CSF from patients with all forms of FTD, with the most pronounced reductions observed in symptomatic MAPT mutation carriers. Furthermore, we demonstrated plasma NfL was significantly positively correlated with disease severity as measured by CDR+NACC FTLD SB in genetic forms of FTD and CSF NPTXR was significantly negatively correlated with CDR+NACC FTLD SB in symptomatic GRN and MAPT mutation carriers.
UNASSIGNED: In conclusion, our comprehensive investigation replicated alterations in biofluid biomarkers indicative of
lysosomal function, glial activation, synaptic and neuronal health across sporadic and genetic forms of FTD and unveiled novel insights into the dysregulation of these biomarkers within brain tissues from patients with GRN mutations. The observed correlations between biomarkers and disease severity open promising avenues for prognostic applications and for indicators of drug efficacy in clinical trials. Our data also implicated a complicated relationship between biofluid and tissue biomarker changes and future investigations should delve into the mechanistic underpinnings of these biomarkers, which will serve as a foundation for the development of targeted therapeutics for FTD.